Cells normally maintain a balance between protein synthesis, folding, trafficking, aggregation, and degradation, referred to as protein homeostasis, utilizing sensors and networks of pathways [Sitia et al., Nature 426: 891-894, 2003; Ron et al., Nat Rev Mol Cell Biol 8: 519-529, 2007]. The cellular maintenance of protein homeostasis, or proteostasis, refers to controlling the conformation, binding interactions, location and concentration of individual proteins making up the proteome. Protein folding in vivo is accomplished through interactions between the folding polypeptide chain and macromolecular cellular components, including multiple classes of chaperones and folding enzymes, which minimize aggregation [Wiseman et al., Cell 131: 809-821, 2007]. Metabolic enzymes also influence cellular protein folding efficiency because the organic and inorganic solutes produced by a given compartment effect polypeptide chain salvation through non-covalent forces, including the hydrophobic effect, that influences the physical chemistry of folding. Metabolic pathways produce small molecule ligands that can bind to and stabilize the folded state of a specific protein, enhancing folding by shifting folding equilibria [Fan et al., Nature Med., 5, 112 (January 1999); Hammarstrom et al., Science 299, 713 (2003)]. Whether a given protein folds in a certain cell type depends on the distribution, concentration, and subcellular localization of chaperones, folding enzymes, metabolites and the like [Wiseman et al.]. Human loss of function diseases are often the result of a disruption of normal protein homeostasis, typically caused by a mutation in a given protein that compromises its cellular folding, leading to efficient degradation [Cohen et al., Nature 426: 905-909, 2003]. Human gain of function diseases are similarly frequently the result of a disruption in protein homeostasis leading protein aggregation [Balch et al. (2008), Science 319: 916-919].
At the cellular level, the heat shock response protects cells against a range of acute and chronic stress conditions [Westerheide et al., J Biol. Chem. 280(39): 33097 (2005)]. The heat shock response (HSR) is a genetic response to environmental and physiological stressors resulting in a repression of normal cellular metabolism and a rapid induction of heat shock protein (HSP) genes expressing molecular chaperones, proteases and other proteins that are useful for protection and recovery from cellular damage as a result of protein misfolding and aggregation [Westerheide et al.]. The heat shock response is mediated by the transcription factor, heat shock factor-1 (HSF-1). Although the HSR protects cells against damage caused by various stressors, accumulation of large amounts of HSPs can be detrimental for cell growth and division [Morimoto et al. (1998), Genes Dev. 12, 3788].
Both dysfunction in proteostasis and the heat shock response have been implicated in a diverse range of diseases including for example, cancer, neurodegenerative disease, metabolic diseases, inflammatory disease and cardiovascular disease. There remains a need in the art for therapeutic approaches to treat conditions associated with proteostasis dysfunction and/or altered induction of heat shock proteins.